Rheumatic fever is a sequella of a group A streptococcal infection and although the exact mechanisms of pathogenesis are unknown, it has been suggested to be due to an autoimmune mechanism related to biological mimicry between the streptococcus and human tissues. The streptococcal antigen(s) which evoke the production of auto-antibodies have been virtually unknown as have been their corresponding tissue antigen(s). Even less is known about how these antibodies might be stimulated or regulated. The work proposed focuses on one major goal to study the molecular and immunological basis of the cross reactions between streptococci and tissue antigens, especially myosin, with emphasis on the study of the human auto-antibodies and the production of specifc idiotypes and anti-idiotypes. Recent work supports the hypothesis that B cell clones against myosin may be stimulated by group A streptococci. The goal to study the molecular and immunological basis of cross reactions will be accomplished by a) the use of murine monoclonal antibodies against streptococci and myosin to probe peptides of myosin, streptococcal M proteins and membrane proteins such as ATPase to identify the cross reactive determinant(s) or structures, b) the study of antibodies from human sera from complicated and uncomplicated streptococcal diseases and their reaction with streptococci and myosin, c) the study of a panel of human monoclonal antibodies reactive with myosin and streptococci, including comparison with murine monoclonal antibodies and production of anti-idiotype sera to use as a probe for the presence of certain idiotypes in human sera, d) the production of synthetic peptides to study the antigenic and immunogenic specificity of these antigens and if necessary production of complementary DNA probes of these peptides to screen for these sequences in nature, and e) a molecular biology approach to identification and eventual cloning of streptococcal genes specifying cross-reactive antigens. Merits of this work include not only the elucidation of streptococcal cross reactive determinants and counterpart tissue antigens, but also will provide insight into the production and regulation of autoimmune phenomena that may be related to amplification or de-regulation of the immune system by infectious agents such as streptococci.